One third of U.S. adults are obese and at risk to develop type-2 diabetes, yet few effective treatments exist to promote healthy body weight. Improved understanding of the physiologic mechanisms that control energy balance is needed to develop treatments for obesity. Neurons in the lateral hypothalamic area (LHA) of the brain exert opposing control of feeding and energy balance by engaging dopamine (DA) neurons in the ventral tegmental area (VTA). DA release from the VTA regulates goal-driven physical activity and palatable food- seeking, behaviors that are disrupted in, and contribute to obesity. The Leinninger lab has begun to characterize a population of LHA neurons that expresses neurotensin (Nts), a neuropeptide that promotes DA release, suppresses feeding and increases locomotor activity. LHA Nts neurons project to the VTA, where many DA neurons express neurotensin receptor-1 (NtsR1). In contrast to other LHA neuronal sub-types that promote feeding, LHA Nts neurons respond to anorectic cues and are poised to suppress feeding. I therefore hypothesize that LHA Nts neurons engage the mesolimbic DA system to restrain food intake and increase physical activity, thus favoring negative energy balance. In Aim 1, I will define the neuronal circuit by which Nts and NtsR1 neurons engage the DA system. In Aim 2, I will selectively activate LHA Nts neurons to test the hypothesis that action via the LHA Nts neuronal circuit suppresses food intake and promotes locomotor activity to induce weight loss. Via my co-sponsors Dr. Gina Leinninger and Dr. Cheryl Sisk, I will learn to combine novel genetic reagents, pharmacogenetics, metabolic phenotyping and neurobehavioral paradigms to determine the role of the LHA Nts neuronal circuit in energy balance. Training in these state-of- the-art techniques that bridge metabolism and neuroscience will enable me to complete this proposal and are essential skills to promote my development into a physician-scientist studying and treating obesity.